tbuckley/cabot-search huggingface dataset:
P1094: SAFETY AND EFFICACY OF ACALABRUTINIB, BENDAMUSTINE, AND RITUXIMAB IN PATIENTS WITH TREATMENT-NAIVE OR RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA: PHASE IB TRIAL
Authors: Tycel Phillips, Michael Wang, Tadeusz Robak, David Gallinson, Don Stevens, Krish Patel, Safaa Ramadan, Chuan-Chaun Wun, Wojciech Jurczak, Stephen D. Smith
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) plus rituximab (R) is used for treatment-naive (TN) and R/R MCL. Aims: We present updated data on safety and efficacy of triple combination ABR in patients with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-day cycles, maintenance A+R for up to 2 years (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 patients were enrolled (TN, n=18; R/R, n=20) with median age 66 years (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease >5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R patients had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN patients and 4 (20.0%) R/R patients were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN patients and 17 (85.0%) R/R patients, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN patients and 13 (65.0%) R/R patients. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 patient outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN patients and 3 (15.0%) R/R patients. Grade ≥3 hypertension was reported in 3 (16.7%) TN patients and 2 (10.0%) R/R patients. Five TN patients died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R patients died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 months in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 months) and 28.6 months and NE, respectively, in the R/R cohort (median follow-up 20.4 months). Summary/Conclusion: Triple-combination ABR was tolerable and effective in patients with TN or R/R MCL.Keywords: Targeted therapy, Phase I, Mantle cell lymphoma, Triple therapy
PB1756: EPIDEMIOLOGY OF ACUTE LYMPHOBLASTIC LEUKAEMIA: A RETROSPECTIVE 6-YEAR SINGLE CENTRE EXPERIENCE
Authors: Jora Kociaj, Liri Seraj, Shaqir Qerama
Journal: HemaSphere (2023)

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: Acute Lymphoblastic Leukaemia (ALL) is a type of blood cancer which affects the bone marrow and the peripheral blood, resulting in an overproduction of immature white blood cells called lymphoblasts or leukaemic blasts. Epidemiology of ALL varies in different countries. This is the first study to evaluate the incidence and epidemiology of ALL in Albania. Aims: The aim of this study is to identify the epidemiology and incidence of ALL in Albania. Methods: The following study is a 6-year retrospective study. Patients diagnosed for the first time with ALL between January 2016 and December 2021, at the University Hospital Center Mother Teresa of Tirana, Albania, over 14 years of age were included in this study. The diagnosis was confirmed by the bone marrow aspiration with at least 20% lymphoblasts in the marrow, immunophenotyping of the marrow. The patients were classified into subgroups according to their gender, age and ALL subtype. Statistical analysis of this study was performed using SPSS. Results: 127 new cases were diagnosed during this time frame. Of all cases a slight dominance of males towards females was noticed, 59.1% and 40.9% respectively. Around 26% of all cases were diagnosed before the age of 25. The numbers dropped as the age group went up, to achieve a second peak around the 56-65 years of age, followed by a lowest point at the oldest age group, 76- 84. The incidence of ALL in Albania is 4.5 per 100.000 inhabitants. Summary/Conclusion: Males are more likely to develop ALL in Albania compared to females, which is comparable to studies performed in other countries. The incidence of ALL in Albania is considerably higher than other European countries.Keywords: ALL, Epidemiology
P1234: A PROGNOSTIC MODEL BASED ON GENE EXPRESSION PARAMETERS PREDICTS A BETTER RESPONSE TO BORTEZOMIB-CONTAINING IMMUNOCHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Adrian Mosquera-Orgueira, Jose Angel Diaz Arias, Rocio Serrano Martin, Victor Portela Piñeiro, Miguel Cid Lopez, Andres Peleteiro Raindo, Laura Bao Perez, Marta Sonia Gonzalez Perez, Manuel Mateo Perez Encinas, Maximo Francisco Fraga Rodriguez, Juan Carlos Vallejo Llamas, Jose Luis Bello Lopez
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: Diffuse Large B-cell Lymphoma (DLBCL) represents the most frequent type of aggressive mature lymphoid neoplasm. Roughly 60% of fit patients can be cured with upfront immunochemotherapy, whereas the remaining patients develop relapsed or refractory disease, which is associated with adverse survival. Risk stratification in DLBCL has been traditionally based on clinical risk scores Other strategies have been explored based on the identification of novel molecular features, such as mutational profiles and gene expression signatures. Recently, we developed the LymForest-25 profile, which provides a personalized survival risk prediction based on the integration of transcriptomic and clinical features using an artificial intelligence system. Aims: In the present report, we studied the relationship between the molecular variables included in LymForest-25 in the context of the data released by the REMoDL-B trial, which evaluated the addition of bortezomib to the standard treatment (R-CHOP) in the upfront setting of DLBCL (Davies et al, 2022). Methods: We retrained the machine learning model of survival on the group of patients treated with R-CHOP (N=469) and then made survival predictions for those patients treated with bortezomib plus R-CHOP (N=459). A random forest model of survival was constructed according to previous specifications (Mosquera et al, 2022), and an out-of-bag estimate was used for optimism adjustment. Predictions were based on results of the survival function, and the landmark of 2-year survival was selected as the prediction point because most lymphoma-related mortality is concentrated in this period (Jakobsen et al, 2017). Results: According to our results, the RB-CHOP scheme achieved a 30% reduction in the risk of progression or death for the 50% of DLBCL patients at higher molecular risk (p-value 0.03; Figure 1A). This effect was even more pronounced among patients in the higher 33% of risk (p-value 0.03, Hazard Ratio 0.66, Figure 1C). Consistently, no statistically significant difference between R-CHOP and RB-CHOP was observed for patients in the lower 50% (Figure 1B) and 66% (Figure 1D) of patients, respectively. Summary/Conclusion: Our results indicate that a machine learning modeling of risk in patients with DLBCL treated with R-CHOP can be useful to identify groups of patients who are predisposed to respond better to the addition of bortezomib, potentially expanding the effectiveness of this treatment to a wider patient population as compared with other previously defined risk groups.Keywords: Bortezomib, Treatment, Prediction, Diffuse large cell lymphoma
PB1815: ADDITIONAL СYTOGENETIC ABNORMALITIES IN ADULT ACUTE MYELOID LEUKEMIA WITH T(8;21)(Q22;Q22)
Authors: Olena Zotova, Olha Shalay, Anna Lukianova, Maria Valchuk, Yuriy Karol, Volodymyr Loginsky
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: A reciprocal translocation involving chromosomes 8 and 21: t(8;21)(q22;q22) is one of the most frequent genetic aberration in adult acute myeloid leukemia (AML) and found in 5-10% of patients. Additional chromosomal abnormalities are often found (60-70%) in association with t(8;21)(q22;q22). The most common are: loss of X or Y, del(9q), trisomy of 4, 8 or 21 and others. These genetic abnormalities are important factors in determining response to chemotherapy as well as outcome in AML. Aims: Aim of this study was to detect additional chromosomal abnormalities in adult AML patients with t(8;21)(q22;q22) and determine frequency of them. Methods: Cytogenetic investigations of bone marrow and/or peripheral blood cells from 135 adult patients with AML were performed. The methods of conventional cytogenetics (GTG) and fluorescence in situ hybridization (FISH) were used. Cytogenetic methods were performed using standard techniques and karyotypes were described according to the International System for Human Cytogenetic Nomenclature. Results: Cytogenetic investigations were performed in 135 patients with AML. Chromosomal aberrations of various kinds were found in 80 (59%) cases. Taking into consideration the identified cytogenetic abnormalities AML patients were classified by prognostic groups: the group of patients with adverse cytogenetic markers (3q21q26 rearrangements, t(9;22)(q34;q11), BCR/ABL1 gene, del(5q), -7, complex karyotype (≥3 abnormalities)), the intermediate-risk group without significant markers (rare or atypical abnormalities, normal karyotype) and the group of patients with favorable prognostic factors (t(15;17)(q22;q21), PML/RARа gene, t(8;21)(q22;q22), AML1/ETO gene, inv(16)(p13q22), CBFβ/MYH11 gene). Translocation t(8;21)(q22;q22) was found in 8 (6%) cases. Of them 3 patients (37%) had only t(8;21)(q22;q22), whereas other 5 (63%) – had additional cytogenetic abnormalities. Spectrum of additional chromosomal aberrations was as follows: loss of Y (3 cases), monosomy of 20 (1 case) and del(9q) as part of a complex karyotype (1 case). Presence of the additional/secondary chromosomal aberrations in leukemic cells with t(8;21)(q22;q22) is the sign of clonal evolution and disease progression. Summary/Conclusion: In our study t(8;21)(q22;q22) was found in 6% of AML patients. The additional chromosomal abnormalities associated with t(8;21)(q22;q22), namely loss of Y, monosomy 20 and del(9q), were found in 63% of cases. Presence of the additional/secondary chromosomal aberrations in leukemic cells with t(8;21)(q22;q22) is the sign of clonal evolution and disease progression. Keywords: Acute myeloid leukemia, Cytogenetic abnormalities
P586: POTENTIAL DRUG-DRUG INTERACTIONS OF ANTIFUNGAL PROPHYLAXIS AND MIDOSTAURIN IN FLT3-MUTATED ACUTE MYELOID LEUKEMIA – CLINICAL IMPLICATIONS OF THERAPEUTIC DRUG MONITORING
Authors: Carolin Joisten, Carsten Müller, Sibylle Mellinghoff, Christian Maurer, Karl-Anton Kreuzer, Martin Wiesen, Philipp Koehler, Oliver A. Cornely, Jannik Stemler
Journal: HemaSphere (2023)

Background: Midostaurin is a FLT3-inhibitor for the treatment of acute myeloid leukaemia (AML) that is metabolized via CYP3A4 and therefore has potential for drug-drug interactions (DDI) with triazole antifungals routinely administered for prophylaxis of invasive fungal disease (IFD). We determined midostaurin and posaconazole plasma concentrations and investigated adverse events (AE) resembling DDI when both drugs were administered concomitantly. Aims:Methods: Twice weekly trough levels were performed for both posaconazole and midostaurin with validated LC-MS/MS methods. Demographic and clinical characteristics of patients were collected. Potential DDI of midostaurin were documented and independently reviewed by two physicians and attributed to DDI or otherwise in a five-level scale. Results: Twenty-four patients were eligible for analysis (22 patients with AML, 2 patients with systemic mastocytosis with an associated hematological neoplasm). A high inter- and intra-individual variability of midostaurin and posaconazole plasma exposure was observed. Inter-individual concentrations ranged from <0.01 mg/l to 24.5 mg/l for midostaurin and from <30 µg/l to 2571 µg/l for posaconazole. In the DDI analysis exanthema (1/24; 4,2%) was evaluated as possibly related to increased midostaurin exposure. Prolonged QTc interval on electrocardiogram (2/24; 8,3%), perimyocarditis, hyperbilirubinemia/liver cell necrosis, diarrhea and nausea (each 1/24; 4,2%) were classified as probably related. Midostaurin dose was reduced in one patient by 50% and discontinued in three patients due to severe AE. Six patients (25%) developed IFD (two Aspergillus spp., one coinfection with Aspergillus spp. and Rhizomucor spp. and three possible IFD according to the revised 2019 EORTC/MSG criteria). Five patients had excessively high midostaurin plasma levels over 15 mg/l, however, clinical significance is hard to determine without larger studies. Table 1 Descriptive interaction analysis of patients with high midostaurin plasma exposureSummary/Conclusion: DDI of posaconazole and midostaurin are clinically meaningful. TDM may serve for decision-making when DDI with strong CYP3A4 inhibitors are suspected clinically and could help to individually adapt the doses of both medications to reduce toxicity. Keywords: FLT3, Anti-fungal prophylaxis, AML
PB1820: THE EFFECT OF CONVENTIONAL CHEMOTHERAPY AFTER EXITING QUIESCENT STATE IN ACUTE MYELOID LEUKAEMIA
Authors: Daniel Láinez-González, Ana Belén Alonso-Aguado, Juana Serrano-López, Juan Manuel Alonso-Dominguez
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: One of the main obstacles in the treatment of acute myeloid leukaemia is the relapse of patients after treatment with conventional chemotherapy, whose main target is proliferative cells. A possible explanation may be the existence of leukaemic stem cells in a reversible state of quiescence (outside the cell cycle) that confer chemoresistance. The activation of the Hedgehog, Notch and Wnt/β-catenin pathways seems to favour the maintenance of quiescence, so their inhibition could induce the entry of these cells into the cell cycle and improve the efficacy of conventional chemotherapy such as cytarabine, previously studied by the group, or azacitidine and idarubicin, presented in this study. Aims: Improve conventional chemotherapy cell death after inhibiting quiescence state by targeting Hedgehog, Notch and Wnt/β-catenin signalling pathways. Methods: Three human AML cell lines were used: HL-60, OCI-AML3 and KASUMI-1. The cells were treated for 48h and 72h with the IC50 concentration of Idarrubicin or Azacitidine, previously determined by the group, and different combinations of the drugs Glasdegib, Nirogacestat and PRI-724, inhibitors of the Hedgehog, Notch and Wnt/β-catenin pathways, respectively. To determine the cytotoxicity of the treatments (24 replicates for each treatment), the WST8 agent was used to obtain a measure of absorbance proportional to the number of viable cells. Results: Inhibiting the Notch pathway in combination with idarrubicin decreased the viability of HL60 cell line in 14% compared to control (p < 0.05), in 30% when Hedgehog and Notch pathways were inhibited together (p < 0.001), and in 16% when all three pathways were inhibited (p < 0.01). Combined treatments of azacytidine and signalling pathway inhibitors revealed a reduction in cell viability relative to the monotherapy control of 20% when inhibiting the Notch pathway (p < 0.01) and 18% when inhibiting the Wnt pathway (p < 0.05) in OCI-AML3, and between 12%-24% when all three signalling pathways were inhibited together in both OCI-AML3 and KASUMI1 (p < 0.001) during 72h. Summary/Conclusion: Combinations of chemotherapy with signalling pathway inhibitors during 72h showed a greater reduction in cell viability compared to the monotherapy control. Also, HL60 showed a more sensitive pattern to idarrubicin, while OCI-AML3 and KASUMI1 were more sensitive to azacitidine. The results obtained show a greater efficacy of conventional chemotherapy when Hedgehog, Notch and Wnt/β-catenin pathways are inhibited in acute myeloid leukaemia cell lines.Figure. Cell viability in HL60, OCI-AML3 and KASUMI1 after inhibition of Hedgehog, Notch and Wnt/Beta-catenin signalling pathways in combination with (A-C) idarrubicin and (D-F) azacytidine. P-values: * < 0.05, ** < 0.01, *** < 0.001, **** < 0,0001 Keywords: Acute myeloid leukemia, Cell cycle, Chemotherapy
PB1892: INCREASED INCIDENCE OF SRSF2 MUTATION WITH AGE INDICATING CLONAL HAEMATOPOIESIS IN PATIENTS WITH ACUTE MYELOID LEUKAEMIA: A SINGLE-CENTER EXPERIENCE
Authors: Michelle Richardson, Chrishthuka Kangatharan, Sheraz Bashir, Victor Ling, Hafsana Siddique, Zafar Ullah, Kirubah Selvaraj, Andrew Hodson, Ioana Nitu-Whalley, Mahesh Prahladan
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: The serine and arginine rich splicing factor 2 (SRSF2) gene is frequently mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Based on the European Leukemia Net (ELN) 2022 risk stratification, SRSF2 mutation is classified as an adverse-risk genetic alteration in AML. Recent studies have suggested that SRSF2 mutation is age-related, with a higher prevalence in older AML patients. Aims: To determine the prevalence of SRSF2 mutation in a cohort of AML patients and to evaluate its association with age. Methods: We retrospectively analyzed the genetic data of 51 AML patients diagnosed between January 2018 and December 2022 at East Suffolk and North Essex foundation NHS trust. We performed targeted sequencing of 28 genes frequently mutated in AML using a custom-designed panel. The NGS technique used in this study involved extracting DNA from blood or bone marrow samples and utilizing a targeted TWIST panel to capture exons of 75 Haem-Onc genes. The Illumina NovaSeq was used for sequencing, and GATK and pindel were used for variant calling with a limit of detection of 5% variant allele frequency. The assay does not exclude the presence of variants outside the targeted regions or large insertions/deletions, gene copy number alterations, or gene rearrangements. Results: We found that the SRSF2 gene was mutated in 8 out of 51 patients (15.7%). All 8 patients were aged 60 years or above, with a median age of 73 years. The prevalence of SRSF2 mutation was significantly higher in older AML patients (≥60 years) than in younger patients (≤59 years) (26.7% vs 0%, p=0.028). According to the ELN 2022 risk stratification, all 8 patients with SRSF2 mutation were classified as having an adverse-risk genetic alteration. Summary/Conclusion: Our study confirms the high prevalence of SRSF2 mutation in AML patients, especially in older patients, and its association with adverse-risk group according to the ELN 2022 risk stratification. Given the poor prognosis associated with adverse-risk genetic alterations, SRSF2 mutation should be considered an important prognostic factor in the management of AML. Keywords: Acute myeloid leukemia, Age related clonal hematopoiesis, Mutation analysis, Somatic mutation
PB1986: FIRST-LINE TREATMENT OUTCOMES OF CHRONIC MYELOID LEUKEMIA (CML) PATIENTS IN A REAL-WORLD DATA SETTING IN LEBANON
Authors: Lewis Nasr, Saada Diab, Intissar Yehia, Fadi Nasr
Journal: HemaSphere (2023)

Topic: 8. Chronic myeloid leukemia - Clinical Background: BCR–ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment for CML, leading to a life expectancy that is currently very close to that of age-matched individuals in the general population. Aims: This study aims to describe aspects of CML in a real-world data setting in Lebanon, including responses to first-line treatment with the first-generation TKI imatinib compared to those with the second-generation TKIs dasatinib and nilotinib, and to evaluate the proportion of patients eligible for an attempt to stop TKI treatment. Methods: This is a retrospective observational multi-center study involving Lebanese patients diagnosed with CML between 2003 and 2019. Inclusion criteria were patients older than 18 years, confirmed diagnosis with CML based on BCR-ABL PCR, and available follow-up data in the clinical chart for at least 2 years. Major and deep molecular responses were based on BCR-ABL1 levels; time of attaining these responses and duration of sustained responses were measured. The reason for switching to another TKI was noted (‘treatment failure’ or ‘intolerance’). Eligibility criteria for an attempt to stop TKI were based on the EURO-SKI trial. Imatinib was given at a dose of 400 mg once daily, nilotinib 300 mg twice daily, and dasatinib 100 mg once daily. The choice of treatment was at the discretion of the treating physician in consultation with the patient as per respective financial and supportive care status. SPSS was used for statistical analysis. Results: 54 patients diagnosed with CML between 2003 and 2019. 54 % were males. The median age at diagnosis was 49.00 ± 17.75 years. The most common reason for presentation was incidental leukocytosis (90%). 70% of patients were treated with imatinib and 30% with a second-generation TKI. 14% of patients discontinued their first-line treatment, mainly due to intolerance (10%) or treatment failure (5%). At 24 months, deep molecular response MR4.0 and MR4.5 was achieved at 15.3% and 40.3%, respectively, for imatinib, and 22% and 33.5%, respectively, for second-generation (p=1). Cumulative incidence of MMR at 24 months of treatment reached 88.9%. The 5-year cumulative incidence of eligibility for TKI cessation attempt was 37%. Summary/Conclusion: We report the experience in CML from two health care institutions in Beirut, Lebanon. There was no statistically significant difference in response between the first- and second-generation TKIs. The criteria for an attempt to stop TKI therapy were met by one-third of patients. Keywords: Survival, BCR-ABL, Chronic myeloid leukemia, Real world data